Handbook of Drug Interactions

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Preface
Drug interactions and adverse drug effects have received much attention since studies
published in daily newspapers have shown that they result in upwards of 100,000
Americans each year being hospitalized or remaining hospitalized longer than necessary,
as well as leading to the death of a number of patients. Use of multiple drugs (8–12 on
average in hospitalized patients) is common in a number of therapeutic regimens. In
addition to multiple drug therapy, a patient may have access to several prescribers, and
may have predisposing illnesses or age as risk factors for interactions. Drug interactions
may occur between prescription drugs, but also between food and drug, and chemical
and drug. Whereas some may be adverse, interactions may also be sought to decrease
side effects or to improve therapeutic efficacy.
Combining drugs may cause pharmacokinetic and/or pharmacodynamic interactions.
Pharmacokinetic mechanisms of interaction include alterations of absorption, distribution,
biotransformation, or elimination. Absorption can be altered when drugs that alter pH or
motility are co-administered, as seen with certain antiulcer or antidiarrheal medications,
or when drugs are chelators or adsorbents (tetracyclines and divalent cations,
cholestyramine, and anionic drugs). Distribution variations can result from competition
for protein binding (sulfa drugs and bilirubin binding to albumin) or displacement from
tissue-binding sites (digitalis and calcium channel blockers or quinidine). Induction of
gene expression (slow), activation or inhibition (much quicker) of liver and extrahepatic
enzymes such as P450, and conjugating enzymes have long found a place of choice in
the literature describing the potential for adverse drug interactions resulting from altered
metabolism. For example, induction is well described with the major anticonvulsant
medications phenytoin, carbamazepine, and barbiturates, whereas inhibition can occur
with antimicrobials from the quinolone, the macrolide, and the azole families. Finally,
excretion can also be modified by drugs that change urinary pH, as carbonic anhydrase
inhibitors do, or change secretion and reabsorption pathways, as probenecid does.
Pharmacokinetic interactions in general result in an altered concentration of active drug
or metabolite in the body, modifying the expected therapeutic response.
A second form of interaction has received little attention because of its modeling
complexity and perhaps the poor understanding of basic physiological, biochemical, and
anatomical substrates for drug action. Pharmacodynamic interactions involve additive
(1 + 1 = 2), potentiating (0 + 1 = 2), synergistic (1 + 1 = 3), or antagonistic (1 + 1 = 0)
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